We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ₁ receptor ligands. All seven ligands exhibited nanomolar affinity for σ₁ receptors (K_i(σ₁) = 0.61 – 12.0 nM) and moderate selectivity toward σ₂ receptors (K_i(σ₂)/ K_i(σ₁) = 2 – 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [¹⁸F]8 was prepared via nucleophilic ¹⁸F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of >99%, and molar activity of 94 – 121 GBq/μmol. Biodistribution studies of [¹⁸F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% - 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ₁ receptor-rich brain areas. These findings suggest that [¹⁸F]8 could be a lead compound for further structural modification to develop potential brain imaging agent for σ₁ receptors.

我们报告了一系列作为选择性 σ ₁受体配体的 1-oxa-8-azaspiro[4.5]decane 和 1,5-dioxa-9-azaspiro[5.5]unedecane 衍生物的设计、合成和评估。所有七个配体均表现出对 σ ₁受体的纳摩尔亲和力 ( K _i (σ ₁ ) = 0.61 – 12.0 nM) 和对 σ ₂受体的中等选择性 ( K _i (σ ₂ )/ K _i (σ ₁ ) = 2 – 44)。在这些配体中具有最佳选择性的化合物8被选择用于放射性标记和进一步评估。放射性配体[ ¹⁸ F] 8通过相应甲苯磺酸盐前体的亲核¹⁸ F-取代制备，总分离放射化学收率为 12-35%，放射化学纯度 >99%，摩尔活度为 94 – 121 GBq/μmol 。 [ ¹⁸ F] 8在小鼠体内的生物分布研究表明，2 分钟后大脑初始摄取量较高。 SA4503 预处理导致脑血比显着降低（30 分钟时为 70% - 75%）。 ICR 小鼠的离体放射自显影显示放射性示踪剂在富含 σ ₁受体的大脑区域中大量积累。这些发现表明，[ ¹⁸ F] 8可能是进一步结构修饰的先导化合物，以开发 σ ₁受体的潜在脑成像剂。